Abstract
The prevalence of swine pandemic H1N1/2009 influenza A virus (SIV-H1N1/2009) in pigs has the potential to generate novel reassortant viruses, posing a great threat to human health. Cellular microRNAs (miRNAs) have been proven as promising small molecules for regulating influenza A virus replication by directly targeting viral genomic RNA. In this study, we predicted potential Sus scrofa (ssc-, swine) miRNAs targeting the genomic RNA of SIV-H1N1/2009 by RegRNA 2.0, and identified ssc-miR-204 and ssc-miR-4331 to target viral HA and NS respectively through dual-luciferase reporter assays. The messenger RNA (mRNA) levels of viral HA and NS were significantly suppressed when newborn pig trachea (NPTr) cells respectively overexpressed ssc-miR-204 and ssc-miR-4331 and were infected with SIV-H1N1/2009, whereas the suppression effect could be restored when respectively decreasing endogenous ssc-miR-204 and ssc-miR-4331 with inhibitors. Because of the importance of viral HA and NS in the life cycle of influenza A virus, ssc-miR-204 and ssc-miR-4331 exhibited an inhibition effect on SIV-H1N1/2009 replication. The antiviral effect was sequence-specific of SIV-H1N1/2009, for the target sites in HA and NS of H5N1 or H9N2 influenza A virus were not conserved. Furthermore, SIV-H1N1/2009 infection reversely downregulated the expression of ssc-miR-204 and ssc-miR-4331, which might facilitate the virus replication in the host. In summary, this work will provide us some important clues for controlling the prevalence of SIV-H1N1/2009 in pig populations.
Highlights
Influenza viruses, which belong to the orthomyxovirus family, are enveloped, single-stranded and negative-sense RNA viruses [1]
Several studies suggested that miRNAs acted in the host antiviral response by altering the expression of host genes required for virus replication [30,31], or by regulating the immune signaling pathways [32,33], or via directly targeting influenza virus genomic RNA [29,33–36]
Cellular miRNAs were shown to play an important role in the life cycle of influenza A virus by directly targeting the viral genomic RNA
Summary
Influenza viruses, which belong to the orthomyxovirus family, are enveloped, single-stranded and negative-sense RNA viruses [1]. All viral proteins play important roles in the life cycle of influenza viruses. Influenza A viruses are among the most important human pathogens that cause yearly epidemics and occasional pandemics. It was worth noting that pigs were considered as the hypothetical “mixing vessel” in which human and avian viruses could reassort, because both human- and avian-type influenza A virus receptors could be expressed on swine epithelial cells in trachea [21]. Novel viruses were generated by the pandemic H1N1/2009 virus with other influenza viruses circulating in pig populations [22–24], which might produce the potential threat to public health. Several studies suggested that miRNAs acted in the host antiviral response by altering the expression of host genes required for virus replication [30,31], or by regulating the immune signaling pathways [32,33], or via directly targeting influenza virus genomic RNA [29,33–36]. In order to explore swine miRNAs that could regulate the SIV-H1N1/2009 replication, we predicted potential miRNAs targeting the viral genomic RNA by bioinformatics method, and identified ssc-miR-204 and ssc-miR-4331 as negative regulators of SIV-H1N1/2009 replication by targeting viral HA and NS respectively
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